Myocardial extracellular volume is a non-invasive tissue marker of heart failure in patients with transposition of the great arteries and systemic right ventricle.

Background: Focal myocardial fibrosis in the systemic right ventricle (RV) is related to ventricular dysfunction and adverse outcome in patients with d-transposition of the great arteries (dTGA) post atrial redirection and those with congenitally corrected TGA (ccTGA). The role of diffuse fibrotic lesions in these conditions remains poorly understood. Our study aimed to investigate diffuse myocardial fibrosis by measuring extracellular volume (ECV) with cardiovascular magnetic resonance (CMR) and to explore correlations between ECV and clinical as well as functional markers of heart failure in patients with TGA and systemic RV. Methods: We prospectively included dTGA and ccTGA patients aged ≥14 years and compared them to healthy controls. Standardized CMR included modified Look-Locker Inversion recovery T1 mapping to quantify diffuse myocardial fibrosis in the systemic RV and the subpulmonary left ventricle (LV). The centerline of RV and LV myocardium was marked with a line of interest tool to determine native and post-contrast T1 for quantification of ECV. Results: In total, 13 patients (dTGA: n = 8, ccTGA: n = 5) with a median age of 30.3 years were enrolled. LV ECV was higher in patients than in controls [34% (30%-41%) vs. 26% (23%-27%), p < 0.001], with values increased above the upper limit of normal in 10/13 patients (77%). RV ECV tended to be higher in patients than in controls, albeit without statistical significance [29% (27%-32%) vs. 28% (26%-29%), p = 0.316]. Patients with elevated LV ECV had lower LV ejection fraction than those with normal ECV (52 ± 5% vs. 65 ± 4%, p = 0.007). Correlations with clinical parameters were not observed. LV ECV was significantly higher than RV ECV (p = 0.016) in the patient group. Conclusions: In this study, LV ECV was significantly increased in TGA patients compared to controls, and was associated with LV dysfunction. Our data suggest that ECV may serve as a non-invasive tissue marker of heart failure in TGA with systemic RV. Further research is necessary to evaluate the prognostic implications and the potential role of ECV in monitoring disease progression and guiding therapy, aiming to maintain LV function or train the LV for subaortic location in TGA patients from infancy to adulthood.

Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment.

The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer's and Parkinson's disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS.

Measuring myocardial extracellular volume of the right ventricle in patients with congenital heart disease.

The right ventricle´s (RV) characteristics-thin walls and trabeculation-make it challenging to evaluate extracellular volume (ECV). We aimed to assess the feasibility of RV ECV measurements in congenital heart disease (CHD), and to introduce a novel ECV analysis tool. Patients (n = 39) and healthy controls (n = 17) underwent cardiovascular magnetic resonance T1 mapping in midventricular short axis (SAX) and transverse orientation (TRANS). Regions of interest (ROIs) were evaluated with regard to image quality and maximum RV wall thickness per ROI in pixels. ECV from plane ROIs was compared with values obtained with a custom-made tool that derives the mean T1 values from a "line of interest" (LOI) centered in the RV wall. In CHD, average image quality was good (no artifacts in the RV, good contrast between blood/myocardium), and RV wall thickness was 1-2 pixels. RV ECV was not quantifiable in 4/39 patients due to insufficient contrast or wall thickness < 1 pixel. RV myocardium tended to be more clearly delineated in SAX than TRANS. ECV from ROIs and corresponding LOIs correlated strongly in both directions (SAX/TRANS: r = 0.97/0.87, p < 0.001, respectively). In conclusion, RV ECV can be assessed if image quality allows sufficient distinction between myocardium and blood, and RV wall thickness per ROI is ≥ 1 pixel. T1 maps in SAX are recommended for RV ECV analysis. LOI application simplifies RV ECV measurements.

Single breath-hold saturation recovery 3D cardiac T1 mapping via compressed SENSE at 3T.

OBJECTIVES: To propose and validate a novel imaging sequence that uses a single breath-hold whole-heart 3D T1 saturation recovery compressed SENSE rapid acquisition (SACORA) at 3T. METHODS: The proposed sequence combines flexible saturation time sampling, compressed SENSE, and sharing of saturation pulses between two readouts acquired at different RR intervals. The sequence was compared with a 3D saturation recovery single-shot acquisition (SASHA) implementation with phantom and in vivo experiments (pre and post contrast; 7 pigs) and was validated against the reference inversion recovery spin echo (IR-SE) sequence in phantom experiments. RESULTS: Phantom experiments showed that the T1 maps acquired by 3D SACORA and 3D SASHA agree well with IR-SE. In vivo experiments showed that the pre-contrast and post-contrast T1 maps acquired by 3D SACORA are comparable to the corresponding 3D SASHA maps, despite the shorter acquisition time (15s vs. 188s, for a heart rate of 60 bpm). Mean septal pre-contrast T1 was 1453 ± 44 ms with 3D SACORA and 1460 ± 60 ms with 3D SASHA. Mean septal post-contrast T1 was 824 ± 66 ms and 824 ± 60 ms. CONCLUSION: 3D SACORA acquires 3D T1 maps in 15 heart beats (heart rate, 60 bpm) at 3T. In addition to its short acquisition time, the sequence achieves good T1 estimation precision and accuracy.

Z-score mapping for standardized analysis and reporting of cardiovascular magnetic resonance modified Look-Locker inversion recovery (MOLLI) T1 data: Normal behavior and validation in patients with amyloidosis.

BACKGROUND: T1 mapping using modified Look-Locker inversion recovery (MOLLI) provides quantitative information on myocardial tissue composition. T1 results differ between sites due to variations in hardware and software equipment, limiting the comparability of results. The aim was to test if Z-scores can be used to compare the results of MOLLI T1 mapping from different cardiovascular magnetic resonance (CMR) platforms. METHODS: First, healthy subjects (n = 15) underwent 11 combinations of native short-axis T1 mapping (four CMR systems from two manufacturers at 1.5 T and 3 T, three MOLLI schemes). Mean and standard deviation (SD) of septal myocardial T1 were derived for each combination. T1 maps were transformed into Z-score maps based on mean and SD values using a prototype post-processing module. Second, Z-score mapping was applied to a validation sample of patients with cardiac amyloidosis at 1.5 T (n = 25) or 3 T (n = 13). RESULTS: In conventional T1 analysis, results were confounded by variations in field strength, MOLLI scheme, and manufacturer-specific system characteristics. Z-score-based analysis yielded consistent results without significant differences between any two of the combinations in part 1 of the study. In the validation sample, Z-score mapping differentiated between patients with cardiac amyloidosis and healthy subjects with the same diagnostic accuracy as standard T1 analysis regardless of field strength. CONCLUSIONS: T1 analysis based on Z-score mapping provides consistent results without significant differences due to field strengths, CMR systems, or MOLLI variants, and detects cardiac amyloidosis with the same diagnostic accuracy as conventional T1 analysis. Z-score mapping provides a means to compare native T1 results acquired with MOLLI across different CMR platforms.

Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration.

After trauma, regeneration of adult CNS axons is abortive, causing devastating neurologic deficits. Despite progress in rehabilitative care, there is no effective treatment that stimulates axonal growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin 1 (Pfn1) as a coordinator of actin and microtubules (MTs), powering axonal growth and regeneration. In growth cones, Pfn1 increased actin retrograde flow, MT growth speed, and invasion of filopodia by MTs, orchestrating cytoskeletal dynamics toward axonal growth. In vitro, active Pfn1 promoted MT growth in a formin-dependent manner, whereas localization of MTs to growth cone filopodia was facilitated by direct MT binding and interaction with formins. In vivo, Pfn1 ablation limited regeneration of growth-competent axons after sciatic nerve and spinal cord injury. Adeno-associated viral (AAV) delivery of constitutively active Pfn1 to rodents promoted axonal regeneration, neuromuscular junction maturation, and functional recovery of injured sciatic nerves, and increased the ability of regenerating axons to penetrate the inhibitory spinal cord glial scar. Thus, we identify Pfn1 as an important regulator of axonal regeneration and suggest that AAV-mediated delivery of constitutively active Pfn1, together with the identification of modulators of Pfn1 activity, should be considered to treat the injured nervous system.

Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment.

Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental disorder. Using the Gnpat-knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter-selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen-deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen-deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin-associated glycoprotein was associated with the active demyelination phase. Using in vitro myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1-myristyl ether [1-O-tetradecyl glycerol (1-O-TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1-O-TDG treatment rescued myelination in plasmalogen-deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue.

Patient-specific modeling of left ventricular electromechanics as a driver for haemodynamic analysis.

AIMS: Models of blood flow in the left ventricle (LV) and aorta are an important tool for analysing the interplay between LV deformation and flow patterns. Typically, image-based kinematic models describing endocardial motion are used as an input to blood flow simulations. While such models are suitable for analysing the hemodynamic status quo, they are limited in predicting the response to interventions that alter afterload conditions. Mechano-fluidic models using biophysically detailed electromechanical (EM) models have the potential to overcome this limitation, but are more costly to build and compute. We report our recent advancements in developing an automated workflow for the creation of such CFD ready kinematic models to serve as drivers of blood flow simulations. METHODS AND RESULTS: EM models of the LV and aortic root were created for four pediatric patients treated for either aortic coarctation or aortic valve disease. Using MRI, ECG and invasive pressure recordings, anatomy as well as electrophysiological, mechanical and circulatory model components were personalized. RESULTS: The implemented modeling pipeline was highly automated and allowed model construction and execution of simulations of a patient's heartbeat within 1 day. All models reproduced clinical data with acceptable accuracy. CONCLUSION: Using the developed modeling workflow, the use of EM LV models as driver of fluid flow simulations is becoming feasible. While EM models are costly to construct, they constitute an important and nontrivial step towards fully coupled electro-mechano-fluidic (EMF) models and show promise as a tool for predicting the response to interventions which affect afterload conditions.